Understanding normal and abnormal brain development requires knowledge of the cellular events whereby differential experience influences the ontogeny of neural structure and function. Research in this area has achieved new and immediate clinical importance with the increasing use of cochlear implants in congenitally and prelingually hearing impaired infants. This application seeks continued funding for a research program aimed at understanding the cellular events whereby the integrity and activity of the inner influences development of brainstem auditory pathways. Three separate lines of investigation are proposed: 1) We will continue to investigate the hypothesis that intracellular calcium homeostasis plays a key role in regulating the initiation of events leading to transneuronal cell death of brainstem neurons in the neonatal mammalian auditory pathways. Specific studies involve comparing changes in cochlear nucleus neurons following reversible inhibition of auditory nerve activity with changes produced by destruction of the inner ear, studies of calcium homeostasis in normal neurons and those deprived of excitatory input, and studies examining the role of plasma membrane ATPases in the regulation of calcium in deprived neurons. 2) The auditory system, like other sensory systems, is particularly sensitive to peripheral pathology during early development. Our second goal is to further understand the biological basis responsible for this "critical period." We will use normal and mutant mice to examine the contribution of specific genes to these changes in susceptibility. We will use microarray technology to screen for new candidate genes, and then directly assay the new gene products for their role in establishing this critical period. 3) We combine single cell labeling, electrophysiology, and calcium imaging methods to study the cellular mechanisms of afferent regulation of dendritic structure. These studies make use of the unique binaural innervation of n. laminaris cells to allow spatial resolution of the relationships between afferent stimulation, calcium homeostasis, and structural dynamics of dendrites.